Distinct histidine residues control the acid-induced activation and inhibition of the cloned K-ATP channel

The modulation of K-ATP channels during acidosis has an impact on vascular tone, myocardial rhythmicity, insulin secretion, and neuronal excitability. Our previous studies have shown that the cloned Kir6.2 is activated with m ild acidification but inhibited with high acidity. The activation relies on His-175, whereas the molecular basis for the inhibition remains unclear. T o elucidate whether the His-175 is indeed the protonation site and what oth er structures are responsible for the pH-induced inhibition, we performed t hese studies. Our data showed that the His-175 is the only proton sensor wh ose protonation is required for the channel activation by acidic pH. In con trast, the channel inhibition at extremely low pH depended on several other histidine residues including His-186, His-193, and His-216. Thus, proton h as both stimulatory and inhibitory effects on the Kir6.2 channels, which at tribute to two sets of histidine residues in the C terminus.